U.S. patent number 10,696,671 [Application Number 16/314,749] was granted by the patent office on 2020-06-30 for imidazo[1,2-a]pyridine derivatives, methods for preparing the same and use thereof.
This patent grant is currently assigned to Jeil Pharmaceutical Co., Ltd.. The grantee listed for this patent is Jeil Pharmaceutical Co., Ltd.. Invention is credited to Kwangwoo Chun, Eunsung Jang, Jeongmin Kim, Joseph Kim, Hyunho Lee, Chun-Ho Park, Yoonsun Park.
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United States Patent |
10,696,671 |
Kim , et al. |
June 30, 2020 |
**Please see images for:
( Certificate of Correction ) ** |
Imidazo[1,2-A]pyridine derivatives, methods for preparing the same
and use thereof
Abstract
The present disclosure relates to novel imidazo[1,2-a]pyridine
derivatives, and more particularly to imidazo[1,2-a]pyridine
derivatives of Formula 1 ##STR00001## wherein Y.sup.1, Y.sup.2 and
Y.sup.3 are each independently H, halogen, a C.sub.1-C.sub.6
straight chain alkyl unsubstituted or substituted with R.sup.1, or
hydroxy; R.sup.1 is hydroxy; Y.sup.4 is H, C.sub.1-C.sub.6 straight
chain alkyl, or C.sub.1-C.sub.6 alkoxy; and X is H or halogen, and
having an excellent activity of inhibiting gastric acid secretion,
methods for preparing the same, and the use thereof. The
imidazo[1,2-a]pyridine derivatives according to the present
disclosure have gastric acid secretion inhibitory activity, and
thus may be effectively used for the prevention or treatment of
gastrointestinal inflammatory diseases or gastric acid-related
diseases.
Inventors: |
Kim; Jeongmin (Seongnam-si,
KR), Lee; Hyunho (Yongin-si, KR), Chun;
Kwangwoo (Yongin-si, KR), Park; Chun-Ho
(Yongin-si, KR), Jang; Eunsung (Daejeon,
KR), Park; Yoonsun (Yongin-si, KR), Kim;
Joseph (Yongin-si, KR) |
Applicant: |
Name |
City |
State |
Country |
Type |
Jeil Pharmaceutical Co., Ltd. |
Seoul |
N/A |
KR |
|
|
Assignee: |
Jeil Pharmaceutical Co., Ltd.
(Seoul, KR)
|
Family
ID: |
59926389 |
Appl.
No.: |
16/314,749 |
Filed: |
July 4, 2017 |
PCT
Filed: |
July 04, 2017 |
PCT No.: |
PCT/KR2017/007055 |
371(c)(1),(2),(4) Date: |
January 02, 2019 |
PCT
Pub. No.: |
WO2018/008929 |
PCT
Pub. Date: |
January 11, 2018 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20190152971 A1 |
May 23, 2019 |
|
Foreign Application Priority Data
|
|
|
|
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Jul 5, 2016 [KR] |
|
|
10-2016-0085048 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
519/00 (20130101); C07D 471/04 (20130101); A61P
1/04 (20180101) |
Current International
Class: |
C07D
471/04 (20060101); C07D 519/00 (20060101); A61P
1/04 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0033094 |
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Aug 1981 |
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EP |
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2002513024 |
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May 2002 |
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JP |
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10-0043134 |
|
May 2001 |
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KR |
|
2348634 |
|
Mar 2009 |
|
RU |
|
1999/055705 |
|
Nov 1999 |
|
WO |
|
1999/055706 |
|
Nov 1999 |
|
WO |
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2002/020523 |
|
Mar 2002 |
|
WO |
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WO 2004/113339 |
|
Dec 2004 |
|
WO |
|
2006/025716 |
|
Mar 2006 |
|
WO |
|
2007/026916 |
|
Mar 2007 |
|
WO |
|
2007/039464 |
|
Apr 2007 |
|
WO |
|
WO 2007/039464 |
|
Apr 2007 |
|
WO |
|
2007/072146 |
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Jun 2007 |
|
WO |
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WO 2008015196 |
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Feb 2008 |
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WO |
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WO/2018/008929 |
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Jan 2018 |
|
WO |
|
Other References
AU Examination Report for App No. AU 2017293271, dated Mar. 27,
2019 (3 pages). cited by applicant .
ISA/KR, International Preliminary Report on Patentability and
Written Opinion for PCT/KR2017/007055, dated Jan. 8, 2019 (9
pages). cited by applicant .
RU Official Action for App No. RU 2019102925, dated Apr. 29, 2019
(With English translation) (8 pages). cited by applicant .
RU Search Report for App No. RU 2019102925, dated Apr. 22, 2019
(With English translation) (4 pages). cited by applicant .
ISA/KR, International Search Report for PCT/KR2017/007055 (Dec. 12,
2017). cited by applicant .
Havu, N., Digestion, 1986, 35 (Suppl 1), 42-55. cited by applicant
.
Chang Seok Song, Dong II Park, Korean J. med., 2011, 81(1), 6-10.
cited by applicant .
Yang YX, et al., JAMA, 2006, 296, 2947-53. cited by applicant .
Targownik LE, et al., CMAJ, 2008, 179(4), 319-26. cited by
applicant .
Gray SL, et al., Arch Intern Med. 2010, 170(9), 765-71. cited by
applicant .
JP Official Action and Search Report for Pat App No. JP 2018-569003
dated Dec. 10, 2019, 6 pages (with English Translation). cited by
applicant.
|
Primary Examiner: Rodriguez-Garcia; Valerie
Attorney, Agent or Firm: Fish & Richardson P.C.
Claims
The invention claimed is:
1. An imidazo[1,2-a]pyridine derivative represented by the
following formula 1 or a pharmaceutically acceptable salt thereof:
##STR00051## wherein Y.sup.1, Y.sup.2 and Y.sup.3 are each
independently H, halogen, a C.sub.1-C.sub.6 straight chain alkyl
unsubstituted or substituted with R.sup.1, or hydroxy; R.sup.1 is
hydroxy; Y.sup.4 is H, C.sub.1-C.sub.6 straight chain alkyl, or
C.sub.1-C.sub.6 alkoxy; and X is H or halogen.
2. The imidazo[1,2-a]pyridine derivative or the pharmaceutically
acceptable salt thereof according to claim 1, wherein Y.sup.1 is H
or a C.sub.1-C.sub.3 straight chain alkyl substituted with R.sup.1;
Y.sup.2 and Y.sup.3 are each independently H, F, a C.sub.1-C.sub.3
straight chain alkyl unsubstituted or substituted with R.sup.1 or
hydroxy; R.sup.1 is hydroxy; Y.sup.4 is H, C.sub.1-C.sub.3 straight
chain alkyl, or C.sub.1-C.sub.3 alkoxy; and X is H, F, or Cl.
3. The imidazo[1,2-a]pyridine derivative or the pharmaceutically
acceptable salt thereof according to claim 2, wherein y is H;
Y.sup.2 and Y.sup.3 are each independently H, F, a C.sub.1-C.sub.2
straight chain alkyl unsubstituted or substituted with R.sup.1, or
hydroxy; R.sup.1 is hydroxy; Y.sup.4 is H or C.sub.1-C.sub.2
straight chain alkyl; and X is H or F.
4. The imidazo[1,2-a]pyridine derivative or the pharmaceutically
acceptable salt thereof according to claim 3, wherein Y.sup.1 is H;
Y.sup.2 and Y.sup.3 are each independently H, F, methyl,
hydroxymethyl, or hydroxy; Y.sup.4 is H or methyl; and X is H or
F.
5. The imidazo[1,2-a]pyridine derivative or the pharmaceutically
acceptable salt thereof according to claim 1, wherein the
derivative represented by formula 1 is selected from the group
consisting of the following compounds: 1)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}(3--
hydroxyazetidin-1-yl)methanone; 6)
azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyr-
idin-6-yl}methanone; 7)
{8-[(2,6-dimethyl)benzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}(3-
-fluoroazetidin-1-yl)methanone; 8)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}(3--
methylazetidin-1-yl)methanone; 9)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}(3--
hydroxy-3-methylazetidin-1-yl)methanone; 11)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}[3--
(hydroxymethyl)azetidin-1-yl]methanone; 17)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo
[1,2-a]pyridin-6-yl}[2-(hydroxymethyl)azetidin-1-yl]methanone; 20)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}[3--
(2-hydroxyethyl)azetidin-1-yl]methanone; 23)
{2,3-dimethyl-8-[(2-methylbenzyl)amino]imidazo[1,2-a]pyridin-6-yl}(3-hydr-
oxyazetidin-1-yl)methanone; 24)
{8-[(5-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-hydroxyazetidin-1-yl)methanone; 25)
(3-hydroxyazetidin-1-yl){8-[(2-methoxy-6-methylbenzyl)amino]-2,3-dimethyl-
imidazo[1,2-a]pyridin-6-yl)methanone; 26)
[3-(hydroxymethyl)azetidin-1-yl]{8-[(2-methoxy-6-methylbenzyl)amino]-2,3--
dimethylimidazo[1,2-a]pyridin-6-yl)}methanone; 27)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-hydroxyazetidin-1-yl)methanone; 28) azetidin-1-yl
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l)}methanone; 29)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-fluoroazetidin-1-yl)methanone; 30)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-methylazetidin-1-yl)methanone; 31)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-hydroxy-3-methylazetidine-1-yl)methanone; 33)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-y-
l}(3-(hydroxymethyl)azetidin-1-yl)methanone; 34)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-hydroxyazetidin-1-yl)methanone; 35)
azetidin-1-yl{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-a]pyridin-6-yl}methanone; 36)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-fluoroazetidin-1-yl)methanone; 37)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-methylazetidin-1-yl)methanone; 38)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-hydroxy-3-methylazetidin-1-yl)methanone; 39)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone; 41)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-hydroxyazetidin-1-yl)methanone; 42)
azetidin-1-yl{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-a]pyridin-6-yl}methanone; 43)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-fluoroazetidin-1-yl)methanone; 44)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone; 45)
azetidin-1-yl{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-a]pyridin-6-yl}methanone; 46)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-hydroxyazetidin-1-yl]methanone; 47)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}(3-fluoroazetidin-1-yl)methanone; and 48)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-
-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone.
6. A pharmaceutical composition for treating gastrointestinal
inflammatory disease or a gastric acid-related disease, the
composition containing, as an active ingredient, an
imidazo[1,2-a]pyridine derivative or a pharmaceutically acceptable
salt thereof according to claim 1.
7. The pharmaceutical composition of claim 6, wherein the
gastrointestinal inflammatory disease or the gastric acid-related
disease is selected from the group consisting of peptic ulcer,
gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug
(NSAID)-induced ulcer, Helicobacter pylori infection, functional
indigestion, Zollinger-Ellison syndrome, gastritis,
gastroesophageal reflux disease (GERD), and nonerosive reflux
disease (NERD).
8. A method for treating a disease caused by excessive secretion of
gastric acid, the method comprising administering a therapeutically
effective amount of an imidazo[1,2-a]pyridine derivative or a
pharmaceutically acceptable salt thereof according to claim 1.
Description
TECHNICAL FIELD
The present disclosure relates to imidazo[1,2-.alpha.]pyridine
derivatives that exhibit an excellent activity of inhibiting
gastric acid secretion, methods for preparing the same, and the use
thereof.
BACKGROUND ART
Gastrointestinal inflammatory diseases or gastric acid-related
diseases, including peptic ulcer, gastric and duodenal ulcer,
gastroesophageal reflux disease (GERD), nonerosive reflux disease
(NERD) and the like, are the most common gastrointestinal diseases
that affect most people in the world, including Korea.
Antiulcer agents, which are classified as agents for treating such
diseases, are divided into two categories: drugs that inhibit
aggressive factors such as gastric acid or pepsin; and drugs that
enhance defensive factors such as sucralfate or misoprostol. Among
these a representative therapeutic agents, various drugs have been
used in the past as agent to inhibit aggressive factors such as
antacids, anticholinergic drugs, H.sub.2 receptor antagonists,
proton pump inhibitors (PPIs) and the like. However, currently,
proton pump inhibitor (PPI) drugs represented by Omeprazole,
Lansoprazole, Pantoprazole, Raveprazole and the like are leading
the market.
The proton pump is H.sup.+/K.sup.+-ATPase that releases H.sup.+
into parietal cells and absorbs K.sup.+ in the final stage of a
gastric acid secretion response caused by binding of various acid
secretion stimulators (histamine, acetylcholine, gastrin and the
like) to their receptors present in parietal cells in vivo. Thus,
proton pump inhibitors (PPIs) are drugs that inhibit gastric acid
secretion by inhibiting the H.sup.+/K.sup.+-ATPase of parietal
cells, which is the final stage of gastric acid secretion. These
proton pump inhibitors (PPIs) are more effective and long-lasting
in inhibiting gastric acid compared to prior drugs, and thus have
been widely used for the past 20 years as therapeutic agents
against peptic ulcer, gastric and duodenal ulcer, gastritis,
gastroesophageal reflux disease (GERD) and the like. In particular,
gastroesophageal reflux disease (GERD) is a chronic recurrent
disease whose patients recently have rapidly increased in number,
and it is an inflammatory disease that causes esophageal
(adenocarcinoma) through the Barrett's esophagus when progressing
to a chronic stage. The treatment rate of this gastroesophageal
reflux disease (GERD) has increased rapidly since launching of
proton pump inhibitors (PPIs).
However, it was reported that, since existing proton pump
inhibitors (PPIs) are converted to an active sulfenamide form by
acid secretion, and then bind irreversibly to the cysteine residues
of H.sup.+/K.sup.+-ATPase to thereby inhibit gastric acid secretion
for a long period of time, they may cause adverse effects,
including gastric bacterial growth, stimulation of proton pump
expression, and tumor cell formation due to hypergastrinemia [Havu
N, Digestion, 1986, 35 (Suppl 1), 42-55; Chang Seok Song, Dong II
Park, Korean J Med., 2011, 81 (1), 6-10]. Furthermore, it was
recently reported that, when these proton pump inhibitors (PPIs)
are used over a long period of time, they inhibit calcium
absorption ability and bone cell growth due to gastric acid
inhibition, thereby increasing the risk of fractures of the hip
joint, carpus and spine [Yang Y X, et al., JAMA, 2006, 296,
2947-53; Targownik L E, et al., CMAJ, 2008, 179 (4), 319-26; Gray S
L, et al., Arch Intern Med. 2010, 170 (9), 765-71]. In addition,
due to an increase in the elderly population, the use of
nonsteroidal anti-inflammatory drugs (NSAIDs) has increased, and
the development of various medical technologies has led to an
increase in survival rate against various diseases, resulting in an
increase in the number of patients with peptic ulcer and
gastroesophageal reflux disease (GERD) induced by various causes.
Furthermore, the number of patients refractory to proton pump
inhibitors (PPIs) has also increased in spite of the very effective
therapeutic ability of the proton pump inhibitors (PPIs).
Accordingly, among recent proton pump inhibitors (PPIs), there is
an increasing interest and need for potassium competitive acid
blocker (P-CAB, acid pump antagonist) drugs having a mechanism by
which they bind reversibly to the K.sup.+ binding site of
H.sup.+/K.sup.+-ATPase to inhibit acid secretion in a
potassium-competitive manner. Particularly, it is expected that
unlike the irreversible proton pump inhibitors (PPIs), the
reversible potassium competitive acid blockers (P-CABs) will
exhibit fast efficacy in view of their mechanism, will be easily
taken before or after a meal, and will be very effective in
nighttime symptoms, which is a problem of irreversible proton pump
inhibitors.
The present disclosure also relates to reversible proton pump
inhibitors (P-CABs), and typical examples of reversible proton pump
inhibitors known in the art include pyrrole derivative TAK-438
[Takeda Pharmaceutical Co. Ltd.; WO2007/026916],
pyrrolo[2,3-c]pyridine YH-4808 [Yuhan Corp.; WO2006/025716],
1H-benzo[d]imidazole derivative CJ-12420 [Pfizer Inc., Japan,
Raqualia Pharma Inc.; WO2007/072146], and
imidazo[1,2-.alpha.]pyridine derivative AZD0865 [AstraZeneca AB;
WO99/55705 and WO99/55706].
Accordingly, the present inventors have studied to develop
low-molecular-weight reversible proton pump inhibitors that can be
effectively used for the prevention or treatment of
gastrointestinal inflammatory diseases or gastric acid-related
diseases, including peptic ulcer, gastric and duodenal ulcer,
gastritis, gastroesophageal reflux disease (GERD), nonerosive
reflux disease (NERD) and the like. As a result, the present
inventors have prepared novel imidazo[1,2-.alpha.]pyridine
derivatives during such studies and have found that these
derivatives exhibit excellent proton pump inhibitory activity,
thereby completing the present disclosure.
DISCLOSURE OF INVENTION
Technical Problem
It is an object of the present disclosure to provide an
imidazo[1,2-.alpha.]pyridine derivative having an excellent
activity of inhibiting gastric acid secretion, and a method for
preparing the same.
Another object of the present disclosure is to provide a
pharmaceutical composition for preventing or treating a disease
caused by excessive secretion of gastric acid, the composition
containing the imidazo[1,2-.alpha.]pyridine derivative as an active
ingredient.
Still another object of the present disclosure is to provide the
use of the imidazo[1,2-.alpha.]pyridine derivative for prevention
or treatment of a disease caused by excessive secretion of gastric
acid.
Yet another object of the present disclosure is to provide a method
for preventing or treating a disease caused by excessive secretion
of gastric acid, the method comprising administering the
imidazo[1,2-.alpha.]pyridine derivative.
Solution to Problem
To achieve the above objects, the present inventors have found that
novel imidazo[1,2-.alpha.]pyridine derivatives are prepared and
these derivatives are effective in the treatment of diseases caused
by gastric acid excess secretion by inhibiting the secretion of
gastric acid.
Imidazo[1,2-.alpha.]Pyridine Derivatives
The present disclosure provides an imidazo[1,2-.alpha.]pyridine
derivative represented by the following formula 1 or a
pharmaceutically acceptable salt thereof:
##STR00002## wherein
Y.sup.1, Y.sup.2 and Y.sup.3 are each independently H, halogen,
C.sub.1-C.sub.6 straight or branched chain alkyl unsubstituted or
substituted with R.sup.1, hydroxy, C.sub.1-C.sub.6 alkoxy
unsubstituted or substituted with R.sup.2, or -A-B, or Y.sup.2 and
Y.sup.3 may be bonded to each other to a form a 4- to 6-membered
heterocyclic ring containing one or two heteroatoms selected from
the group consisting of N, O and S;
R.sup.1 and R.sup.2 are each independently hydroxy or
C.sub.1-C.sub.6 alkoxy;
A is --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--, or
--S(.dbd.O).sub.2--;
B is H or C.sub.1-C.sub.6 straight or branched chain alkyl;
Y.sup.4 is H, C.sub.1-C.sub.6 straight or branched chain alkyl, or
C.sub.1-C.sub.6 alkoxy; and
X is H or halogen.
According to one embodiment of the present disclosure,
Y.sup.1 may be H or C.sub.1-C.sub.3 straight or branched chain
alkyl unsubstituted or substituted with R.sup.1;
Y.sup.2 and Y.sup.3 are each independently H, F, Cl,
C.sub.1-C.sub.3 straight or branched chain alkyl unsubstituted or
substituted with R.sup.1, hydroxy, C.sub.1-C.sub.3 alkoxy
unsubstituted or substituted with R.sup.2, or -A-B, or Y.sup.2 and
Y.sup.3 may be bonded to each other to form a 4- to 6-membered
heterocyclic ring containing one or two heteroatoms selected from
the group consisting of N, O and S;
R.sup.1 and R.sup.2 may be each independently hydroxy or
C.sub.1-C.sub.3 alkoxy;
A may be --C(.dbd.O)--, --C(.dbd.O)O--, --OC(.dbd.O)--, or
--S(.dbd.O).sub.2--;
B may be C.sub.1-C.sub.3 straight or branched chain alkyl;
Y.sup.4 may be H, C.sub.1-C.sub.3 straight or branched chain alkyl
or C.sub.1-C.sub.3 alkoxy; and
X may be H, F, or Cl.
According to another embodiment of the present disclosure,
Y.sup.1 may be H;
Y.sup.2 and Y.sup.3 may be each independently H, F, Cl,
C.sub.1-C.sub.2 straight or branched chain alkyl unsubstituted or
substituted with R.sup.1, or hydroxy;
R.sup.1 may be hydroxy;
Y.sup.4 may be H or C.sub.1-C.sub.2 straight or branched chain
alkyl; and
X may be H or F.
According to still another embodiment of the present
disclosure,
Y.sup.1 may be H;
Y.sup.2 and Y.sup.3 may be each independently H, F, methyl,
hydroxymethyl, or hydroxy;
Y.sup.4 may be H or methyl; and
X may be H or F.
In a preferred embodiment, the imidazo[1,2-.alpha.]pyridine
derivative of the present disclosure may be selected from the group
consisting of the following compounds: 1)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-hydroxyazetidin-1-yl)methanone; 2)
1-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridine-
-6-carbonyl}azetidin-3-yl acetate; 3)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-methoxyazetidin-1-yl)methanone; 4)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-ethoxyazetidin-1-yl)methanone; 5)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(2-methoxyethoxy)azetidin-1-yl]methanone; 6)
azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alph-
a.]pyridin-6-yl}methanone; 7)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}(3--
fluoroazetidin-1-yl)methanone; 8)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-methylazetidin-1-yl)methanone; 9)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-hydroxy-3-methylazetidin-1-yl)methanone; 10) methyl
1-{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridine-
-6-carbonyl}azetidine-3-carboxylate; 11)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(hydroxymethyl)azetidin-1-yl]methanone; 12)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(methoxymethyl)azetidin-1-yl]methanone; 13)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-fluoro-3-(hydroxymethyl)azetidin-1-yl]methanone; 14)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(hydroxymethyl)-3-methylazetidin-1-yl]methanone; 15)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(1-hydroxyethyl)azetidin-1-yl]methanone; 16)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(2-hydroxypropan-2-yl)azetidin-1-yl]methanone; 17)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[2-(hydroxymethyl)azetidin-1-yl]methanone; 18)
1-{1-[8-({2,6-dimethylbenzyl}amino)-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
ine-6-carbonyl]azetidin-3-yl}ethanone; 19)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(methylsulfonyl)azetidin-1-yl]methanone; 20)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}[3-(2-hydroxyethyl)azetidin-1-yl]methanone; 21)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(2,6-diazaspiro[3.3]heptan-2-yl)methanone; 22)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone; 23)
{2,3-dimethyl-8-[(2-methylbenzyl)amino]imidazo[1,2-.alpha.]pyridin-6-yl}(-
3-hydroxyazetidin-1-yl)methanone; 24)
{8-[(5-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-hydroxyazetidin-1-yl)methanone; 25)
(3-hydroxyazetidin-1-yl){8-[(2-methoxy-6-methylbenzyl)amino]-2,3-dimethyl-
imidazo[1,2-.alpha.]pyridin-6-yl)methanone; 26)
[3-(hydroxymethyl)azetidin-1-yl]{8-[(2-methoxy-6-methylbenzyl)amino]-2,3--
dimethyl imidazo[1,2-.alpha.]pyridin-6-yl}methanone; 27)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-hydroxyazetidin-1-yl)methanone; 28) azetidin-1-yl
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}methanone; 29)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-fluoroazetidin-1-yl)methanone; 30)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-methylazetidin-1-yl)methanone; 31)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-hydroxy-3-methylazetidine-1-yl)methanone; 32)
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-methoxy-3-methylazetidin-1-yl)methanone; 33)
{8-[(4-fluoro-2-methylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyrid-
in-6-yl}(3-(hydroxymethyl)azetidin-1-yl)methanone; 34)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-hydroxyazetidin-1-yl)methanone; 35)
azetidin-1-yl{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-.alpha.]pyridin-6-yl}methanone; 36)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-fluoroazetidin-1-yl)methanone; 37)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-methylazetidin-1-yl)methanone; 38)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-hydroxy-3-methylazetidin-1-yl)methanone; 39)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone; 40)
{8-[(4-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}[3-(methoxymethyl)azetidin-1-yl]methanone; 41)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-hydroxyazetidin-1-yl)methanone; 42)
azetidin-1-yl{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-.alpha.]pyridin-6-yl}methanone; 43)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-fluoroazetidin-1-yl)methanone; 44)
{8-[(3-fluoro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone; 45)
azetidin-1-yl{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[-
1,2-.alpha.]pyridin-6-yl}methanone; 46)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}[(3-hydroxyazetidin-1-yl]methanone; 47)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}(3-fluoroazetidin-1-yl)methanone; and 48)
{8-[(3-chloro-2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]p-
yridin-6-yl}[3-(hydroxymethyl)azetidin-1-yl]methanone.
In the present disclosure, pharmaceutically acceptable salts may be
those that are generally used in the art such as acid addition
salts that are formed by pharmaceutically acceptable free acids,
but not limited thereto. The pharmaceutically acceptable free acids
may be organic acids and inorganic acids. The inorganic acids may
include hydrochloric acid, phosphoric acid, sulfuric acid, nitric
acid and the like, and the organic acid may include methanesulfonic
acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid,
maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric
acid, fumaric acid, mandelic acid, propionic acid, citric acid,
lactic acid, glycolic acid, gluconic acid, galacturonic acid,
glutamic acid, glutaric acid, glucuronic acid, aspartic acid,
ascorbic acid, carbonic acid, vinylic acid and the like.
Furthermore, a pharmaceutically acceptable metal salt may be
prepared using a base. For example, an alkali metal or alkaline
earth metal salt of a compound may be prepared by dissolving the
compound in an excess of an alkali metal hydroxide or alkaline
earth metal hydroxide solution, filtering an undissolved compound
salt, and evaporating and drying the filtrate. Herein, a
pharmaceutically acceptable metal salt suitable for pharmaceutical
use is sodium, potassium or calcium salt, but is not limited
thereto.
In addition, the compounds of formula 1 according to the present
disclosure include solvates and hydrates that can be prepared from
pharmaceutically acceptable salts, and all possible optical
isomers, stereoisomers and mixtures thereof also fall within the
scope of the present disclosure. Herein, solvates, hydrates and
stereoisomers of the compounds represented by formula 1 may be
prepared using conventional methods known in the art.
In addition, the compound of formula 1 according to the present
disclosure may be prepared in a crystalline form or an amorphous
form. When the compound of formula 1 is prepared in a crystalline
form, it may optionally be hydrated or solvated.
Methods for Preparation of Imidazo[1,2-.alpha.]Pyridine
Derivatives
The present disclosure provides methods for preparation of the
imidazo[1,2-.alpha.]pyridine derivatives represented by formula 1
or pharmaceutically acceptable salts thereof.
Preferably, the compounds of formula 1 can be prepared by the
method shown in reaction scheme 1 below, but are not limited
thereto. Particularly, any person skilled in the art will
sufficiently understand that the compounds of formula 1 according
to the present disclosure can be prepared by various methods using
known techniques well known in the art.
Reaction scheme 1 shown below show each step of a method for
preparing representative compounds according to the present
disclosure, and various compounds according to the present
disclosure can be prepared by modifications that change reagents,
solvents and reaction sequences, which are used in the preparation
process shown in reaction scheme 1 below. Several compounds
according to the present disclosure can be prepared according to
processes that do not fall within the scope of reaction scheme 1
shown below, and specific processes for preparation of such
compounds will be described in detail in the Examples below.
Preparation Method 1
Specifically, as shown in reaction scheme 1 below, the derivatives
of formula 1 or pharmaceutically acceptable salts thereof can be
prepared by a method comprising the steps of:
1) benzylating a carboxylic acid alkyl ester of formula 2 with
substituted benzyl halide or benzaldehyde to thereby prepare a
compound of formula 3 (step 1);
2) adding an aqueous solution of potassium hydroxide or sodium
hydroxide dropwise to the compound of formula 3 prepared in step 1,
thereby preparing a hydrolyzed carboxylic acid of formula 4 (step
2); and
3) amidating the carboxylic acid of formula 4, prepared in step 2,
with unsubstituted or substituted azetidine by use of a coupling
reagent, thereby preparing the compound of formula 1.
##STR00003##
(wherein Y.sup.1 to Y.sup.4 and X are as defined in formula 1
above, and Alk is an alkyl group such as methyl, ethyl, isopropyl
or the like. Preferably, Alk is isopropyl.)
Each of the method for preparing the compound of formula 1 will now
be described in detail with reference to reaction scheme 1.
In step 1, a carboxylic acid alkyl ester of formula 2, which can be
easily synthesized using a known technique (WO 99/055705 or WO
99/055706), is reacted with substituted benzyl halide (e.g.,
2,6-dimethylbenzyl chloride or 4-fluoro-2-methylbenzyl bromide) in
the presence of a base such as potassium carbonate and a catalytic
amount of sodium iodide, thereby preparing a substituted
benzylamino imidazolopyridine compound of formula 3. This reaction
is benzylation of amine acid compound with benzyl halide and is
performed in the presence of a base that may be used in
benzylation. Examples of a base that may be used for this purpose
include sodium hydride (NaH), potassium carbonate, sodium
carbonate, cesium carbonate, sodium or potassium alkoxides, etc. In
addition, the reaction is preferably performed in the presence of a
solvent that does not adversely affect the reaction, and examples
of this solvent include dichloromethane, chloroform,
tetrahydrofuran, diethylether, toluene, N,N-dimethylformamide or
acetonitrile. The reaction temperature is not particularly limited,
but the reaction may generally be performed at cold temperature or
warm temperature, preferably room temperature or warm
temperature.
In step 2, an aqueous solution of potassium hydroxide or sodium
hydroxide is slowly added dropwise to the compound of formula 3
prepared in step 1, thereby preparing a hydrolyzed carboxylic acid
compound of formula (4). The reaction in step 2 is performed in an
alcohol solvent such as methanol or ethanol, which does not
adversely affect the reaction. The reaction temperature is not
particularly limited, but the reaction is performed at cold
temperature or warm temperature, preferably room temperature or
warm temperature. This reaction may be performed under general
ester hydrolysis conditions.
In step 3, the carboxylic acid compound of formula 4, prepared in
step 2, is amidated with unsubstituted or substituted azetidine by
use of a coupling reagent, thereby preparing the compound of
formula 1. The coupling reagent used may be
[1-(3-dimethylaminopropyl)-3-ethylcarbodiimide] (EDCI),
1,3-dicyclohexyl carbodiimide (DCC), 1,1-carbonyl diimidazole and
the like, which is commercially easily available. Although this
reaction may be performed in the absence of a base, it is
preferably performed in a solvent, such as acetonitrile, dimethyl
formamide or dichloromethane, which does not adversely affect the
reaction, in the presence of a conventional base such as
4-dimethylaminopyridine, pyridine, triethylamine,
diethylisopropylamine, N-methylmorpholine or dimethylphenylamine,
which may be used in amidation. The reaction temperature is not
particularly limited, but the reaction is performed at cold
temperature or warm temperature, preferably room temperature or
warm temperature.
Target compounds produced according to the method shown in reaction
scheme 1 above may be purified using conventional methods, for
example, column chromatography, recrystallization and the like.
The compounds of formula 1 according to the present disclosure may
be prepared into pharmaceutically acceptable salts thereof or
solvates thereof according to conventional methods known in the
art.
Pharmaceutical Composition Containing Imidazo[1,2-.alpha.]Pyridine
Derivative, Use Thereof, and Method for Treating Disease Using the
Same
The present disclosure provides a pharmaceutical composition for
preventing or treating a disease caused by excessive secretion of
gastric acid, the composition containing the
imidazo[1,2-.alpha.]pyridine derivative of formula 1 or a
pharmaceutically acceptable salt thereof.
Examples of the disease caused by excessive secretion of gastric
acid include gastrointestinal inflammatory diseases or gastric
acid-related diseases. The gastrointestinal inflammatory diseases
or gastric acid-related diseases include peptic ulcer, gastric and
duodenal ulcer, nonsteroidal anti-inflammatory drug (NSAID)-induced
ulcer, Helicobacter pylori infection, indigestion, functional
indigestion, Zollinger-Ellison syndrome, gastritis,
gastroesophageal reflux disease (GERD), laryngopharyngeal reflux
disease, nonerosive reflux disease (NERD), visceral referred pain,
cancer, heartburn, vomiting, esophagitis, dysphagia,
hypersalivation, airway obstruction, or asthma.
The imidazo[1,2-.alpha.]pyridine derivative according to the
present disclosure has an excellent activity of inhibiting gastric
acid secretion, and thus may be effectively used for prevention or
treatment of gastrointestinal inflammatory diseases or gastric
acid-related diseases, particularly peptic ulcer, gastric and
duodenal ulcer, gastroesophageal reflux disease (GERD), and
nonerosive reflux disease (NERD).
A pharmaceutical composition containing the compound of the present
disclosure as an active ingredient may be formulated according to
standard pharmaceutical practice to provide oral formulations,
including powders, granules, tablets, capsules, suspensions,
emulsions, syrups and aerosols, formulations for external use,
suppositories, or sterile injectable formulations.
Specifically, the pharmaceutical composition of the present
disclosure may be formulated using diluents or excipients, such as
fillers, extenders, binders, wetting agents, disintegrants,
surfactants, etc., which are commonly used. Solid formulations for
oral administration include tablets, pills, powders, granules,
capsules and the like, and such solid formulations may be prepared
by mixing the compound with at least one or more excipient, for
example, starch, calcium carbonate, sucrose, lactose or gelatin. In
addition to simple excipients, lubricants such as magnesium
stearate or talc may also be used. Liquid formulations for oral
administration include suspensions, solutions, emulsions, and
syrup, and may contain various excipients, for example, wetting
agents, flavoring agents, aromatics and preservatives, in addition
to water and liquid paraffin, which are frequently used simple
diluents. Formulations for parenteral administration include
sterilized aqueous solutions, non-aqueous solutions, suspensions,
emulsions, freeze-dried preparations, and suppositories. As
non-aqueous solvents or suspending agents, propylene glycol,
polyethylene glycol, plant oils such as olive oil, injectable
esters such as ethyl oleate, etc., can be used. For suppositories,
witepsol, Macrogol, Tween 61, cacao butter, laurin fat,
glycerogelatin and the like may be used, but are not limited
thereto.
The preferred dose of the compound of formula 1 according to the
present disclosure or a pharmaceutically acceptable salt thereof
may vary depending on the patient's condition and body weight, the
severity of the disease, the form of drug, and the route and period
of administration, and can be suitably determined by a person
skilled in the art. However, for preferred effects, the compound of
the present disclosure may be administered once or several times a
day at a dose of 0.0001-1000 mg/kg, preferably 0.01-500 mg/kg.
Furthermore, the composition of the present disclosure may contain
the compound of formula 1 in an amount of 0.0001-99 wt %,
preferably 0.01-50 wt %, depending on the mode of
administration.
The pharmaceutical composition of the present disclosure may
further contain, in addition to the compound of formula 1 or a
pharmaceutically acceptable salt thereof, one or more active
ingredients exhibiting a medicinal effect equal or similar to the
compound of formula 1.
Moreover, the pharmaceutical composition of the present disclosure
may be administered by various routes to mammals, including rats,
mice, livestock and humans. All modes of administration are
contemplated, for example, administration can be orally, rectally,
intravenously, intramuscularly, subcutaneously, intrathecally or by
injection into cerebral blood vessels.
The present disclosure also provides the use of the
imidazo[1,2-.alpha.]pyridine derivative for prevention or treatment
of a disease caused by excessive secretion of gastric acid.
For preparation of medicaments, the compound represented by formula
1 may be mixed with a pharmaceutically acceptable adjuvant, diluent
or carrier, and may also be combined with other active ingredients
so as to exhibit synergistic effects.
The present disclosure also provides a method for preventing or
treating a disease caused by excessive secretion of gastric acid,
the method comprising administering an effective amount of the
imidazo[1,2-.alpha.]pyridine derivative to mammals, including
humans. The method for preventing or treating disease according to
the present disclosure also comprises inhibiting or averting
symptoms of the disease as well as addressing the disease itself
prior to the onset of symptoms, by administering the compound of
formula 1. The prophylactic or therapeutic dose of a particular
active ingredient in the management of a disease will vary
depending on the nature and severity of the disease or condition,
and the route by which the active ingredient is administered. The
dose and the dose frequency will also vary according to the age,
body weight, and response of the individual patient. Suitable
dosing regimens can be readily selected by those skilled in the art
with due consideration of such factors. In addition, the method for
preventing or treating disease according to the present disclosure
may further comprise administering a therapeutically effective
amount of an additional active agent assisting in treatment of the
disease, together with administration of the compound of formula 1.
The additional active agent can exhibit a synergistic effect or an
additive effect with the compound of formula 1.
The details mentioned in the pharmaceutical composition, use and
treating method of the present disclosure are applied in the same
manner, unless they are not contradictory to each other.
Advantageous Effects of Invention
Imidazo[1,2-.alpha.]pyridine derivatives according to the present
disclosure can reversibly inhibit the proton pump, and thus can be
effectively used for prevention or treatment of diseases caused by
excessive secretion of gastric acid, particularly peptic ulcer,
gastric and duodenal ulcer, nonsteroidal anti-inflammatory drug
(NSAID)-induced ulcer, Helicobacter pylori infection, functional
indigestion, Zollinger-Ellison syndrome, gastritis,
gastroesophageal reflux disease (GERD), nonerosive reflux disease
(NERD), etc.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a graph showing the long-lasting inhibitory effects of
compounds of the present disclosure against gastric acid secretion
in lumen-perfused rats as a function of time.
MODE FOR THE INVENTION
Hereinafter, preferred examples and test examples will be presented
to help understand the present disclosure. It is to be understood,
however, that these examples and test examples are merely provided
to facilitate understanding of the present disclosure and are not
intended to limit the scope of the present disclosure.
Reference Example 1:
2-(Bromomethyl)-5-fluoro-1,3-dimethylbenzene
To 1-fluoro-3,5-dimethylbenzene (2.0 g, 16.1 mmol), p-formaldehyde
(7.5 g, 250 mmol), hydrogen bromide (33 wt % in acetic acid; 35 ml)
and acetic acid (12 ml, 210 mmol) were sequentially added at room
temperature, followed by stirring for 5 hours. Water was added to
the reaction solution to terminate the reaction, followed by
extraction with diethylether. The organic layer was dried with
anhydrous magnesium sulfate, and then concentrated under reduced
pressure to remove the solvent. The residue was purified by column
chromatography (100% hexane) to afford the title compound (1.0 g,
yield: 30%) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 6.76 (s, 1H), 6.74 (s,
1H), 4.53 (s, 2H), 2.41 (s, 6H).
Reference Example 2: 2-(Chloromethyl)-1-methoxy-3-methylbenzene
Step 1: Synthesis of ethyl 2-methoxy-6-methylbenzoate
Ethyl 2-hydroxy-6-methylbenzoate (1.0 g, 5.6 mmol), methyl iodide
(866 mg, 6.1 mmol), and potassium carbonate (1.5 g, 11.1 mmol) were
dissolved in acetone, and then refluxed for 17 hours. Water was
added to the reaction solution to terminate the reaction, followed
by extraction with dichloromethane. The organic layer was dried
with anhydrous magnesium sulfate, and then concentrated under
reduced pressure to remove the solvent. The residue was purified by
column chromatography (100% hexane) to afford the title compound
(1.1 g, yield: 99%).
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.26-7.21 (m, 1H),
6.80-6.75 (m, 2H), 4.40 (qt, J=14.4, 7.2 Hz, 2H), 3.82 (s, 3H),
2.30 (s, 3H), 1.38 (t, J=7.2 Hz, 3H).
Step 2: Synthesis of (2-methoxy-6-methylphenyl)methanol
Anhydrous tetrahydrofuran (20 ml) was added to aluminum lithium
hydride (LAH, 365 mg, 9.62 mmol) and cooled to 0.degree. C., after
which the compound (1.1 g, 5.6 mmol) prepared in step 1 was
dissolved in anhydrous tetrahydrofuran (30 ml) and slowly added
dropwise thereto at 0.degree. C. The reaction solution was stirred
at room temperature for 2 hours, and an aqueous solution of 15%
sodium hydroxide was added thereto to terminate the reaction. Then,
the reaction solution was filtered through celite and concentrated
under reduced pressure, and the residue was purified by column
chromatography (hexane:ethyl acetate=20:1) to afford the title
compound (775 mg; yield: 91%).
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.20-7.17 (m, 1H), 6.83
(m, 2H), 4.78 (s, 2H), 4.01 (s, 3H), 3.41 (s, 3H).
Step 3: 2-(Chloromethyl)-1-methoxy-3-methylbenzene
The compound (775 mg, 5.1 mmol) prepared in step 2 was dissolved in
dichloromethane (30 ml), and thionyl chloride (1.0 ml, 15.2 mmol)
was slowly added thereto dropwise at room temperature, followed by
stirring for 2 hours. Cold ice water was added to the reaction
solution to terminate the reaction, followed by extraction with
dichloromethane. The organic layer was dried with anhydrous
magnesium sulfate, and then concentrated under reduced pressure to
remove the solvent, thereby obtaining the title compound (804 mg;
yield: 93%).
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.19 (t, J=8.0 Hz, 1H),
6.83 (m, 2H), 4.62 (s, 2H), 3.91 (s, 3H), 3.36 (s, 3H).
Reference Example 3:
1-Chloro-3-(chloromethyl)-2,4-dimethylbenzene
Step 1: Synthesis of 2,6-dimethyl-3-nitrobebzoic acid
To a mixture of concentrated sulfuric acid (8 ml) and 60% nitric
acid (8 ml), 2,6-dimethylbenzoic acid (3.7 g, 24.64 mmol) was added
at 0.degree. C., followed by stirring for 1.5 hours. After
completion of the reaction, water was added to the reaction
solution at the same temperature, followed by stirring for 0.5
hours. The produced solid was filtered under reduced pressure,
washed with water, and then dried, thereby obtaining the title
compound (4.7 g; yield: 98%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.87 (d, J=8.0 Hz, 1H),
7.23 (d, J=7.6 Hz, 1H), 2.58 (s, 3H), 2.48 (s, 3H).
Step 2: Synthesis of methyl 2,6-dimethyl-3-nitrobenzoate
The compound (4.7 g, 24.08 mmol) prepared in step 1 was dissolved
in N,N-dimethylformamide (15 ml), and potassium carbonate (6.7 g,
48.16 mmol) and methyl iodide (6.7 ml, 108.37 mmol) were
sequentially added thereto, followed by stirring overnight at
0.degree. C. The reaction was terminated by addition of cold ice
water, and the reaction solution was extracted with ethyl acetate
and washed with an aqueous solution of sodium chloride. The
separated organic layer was dried with anhydrous sodium sulfate and
concentrated under reduced pressure, and the residue was purified
by column chromatography (hexane:ethyl acetate=4:1) to afford the
title compound (3.8 g; yield 75%) as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.84 (d, J=7.6 Hz, 1H),
7.19 (d, J=8.4 Hz, 1H), 3.96 (s, 3H), 2.46 (s, 3H), 2.36 (s,
3H).
Step 3: Synthesis of methyl 3-amino-2,6-dimethylbenzoate
The compound (3.8 g, 18.16 mmol) prepared in step 2 was dissolved
in ethyl acetate (20 ml) and methanol (20 ml), and 10% palladium
(760 mg, 20 wt %) was added thereto at room temperature, followed
by stirring overnight in an atmosphere of hydrogen gas. After
completion of the reaction, the reaction solution was filtered
through celite and concentrated under reduced pressure, thereby
obtaining the title compound (3 g; yield: 92%) as colorless
oil.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 6.86 (d, J=8.0 Hz, 1H),
6.63 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.55 (br, 2H), 2.19 (s, 3H),
2.08 (s, 3H).
Step 4: Synthesis of methyl 3-chloro-2,6-dimethylbenzoate
To the compound (2.0 g, 11.16 mmol) prepared in step 3, water (20
ml) and concentrated hydrochloric acid (20 ml) were added, followed
by stirring for 10 minutes. The reaction solution was cooled to
-10.degree. C., and a solution of sodium nitrite (810 mg, 11.72
mmol) in water (2 ml) was slowly added dropwise thereto. After 30
minutes, water (10 ml), and a solution of cuprous chloride (1.3 g,
13.39 mmol) in concentrated hydrochloric acid (10 ml) at 0.degree.
C. was slowly added dropwise to the reaction solution at
-10.degree. C., followed by stirring at the same temperature for 1
hour. Next, the reaction solution was heated at 70.degree. C. for 1
hour. Thereafter, the reaction solution was cooled to room
temperature, extracted with ethyl acetate, and washed with an
aqueous solution of sodium chloride, after which the separated
organic layer was dried with anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane:ethyl acetate=10:1) to afford the
title compound (2.2 g; yield 99%) as colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.28 (d, J=8.0 Hz, 1H),
6.98 (d, J=8.0 Hz, 1H), 3.92 (s, 3H), 2.30 (s, 3H), 2.26 (s,
3H).
Step 5: Synthesis of (3-chloro-2,6-dimethylphenyl)methanol
The compound (2.8 g, 14.35 mmol) prepared in step 4 was dissolved
in tetrahydrofuran (30 ml), and lithium aluminum hydride (590 mg,
15.78 mmol) was added to the solution at -78.degree. C., followed
by stirring at room temperature for 4 hours. The reaction was
terminated by addition of a 1N aqueous solution of sodium hydroxide
at 0.degree. C., and the reaction solution was stirred for 30
minutes, and then filtered through celite under reduced pressure
and extracted with dichloromethane. The separated organic layer was
washed with an aqueous solution of sodium chloride, dried with
anhydrous sodium sulfate, and then concentrated under reduced
pressure, thereby obtaining the title compound (1.9 g; yield: 79%)
as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.22 (d, J=8.0 Hz, 1H),
6.97 (d, J=8.4 Hz, 1H), 4.75 (d, J=4.8 Hz, 2H), 2.48 (s, 3H), 2.39
(s, 3H).
Step 6: Synthesis of
1-chloro-3-(chloromethyl)-2,4-dimethylbenzene
The compound (2.0 g, 11.72 mmol) prepared in step 5 was added to
anhydrous dichloromethane (20 ml), and thionyl chloride (1.3 ml,
17.58 mmol) was slowly added dropwise thereto at 0.degree. C.,
followed by stirring at room temperature for 3 hours. After
completion of the reaction, the reaction solution was concentrated
under reduced pressure to remove the solvent and an excess of
thionyl chloride, and the residue was purified by column
chromatography (hexane:ethyl acetate=15:1) to afford the title
compound (1.8 g; yield 83%) as colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.23 (d, J=8.0 Hz, 1H),
6.97 (d, J=8.4 Hz, 1H), 4.64 (s, 2H), 2.47 (s, 3H), 2.39 (s,
3H).
Reference Example 4:
1-Fluoro-3-(chloromethyl)-2,4-dimethylbenzene
Step 1: Synthesis of methyl 3-fluoro-2,6-dimethylbenzoate
To the compound (4.3 g, 23.99 mmol) prepared in step 3 of Reference
Example 3, water (40 ml) and concentrated hydrochloric acid (40 ml)
were added, and the solution was stirred for 10 minutes. The
reaction solution was cooled to -10.degree. C., and a solution of
sodium nitrite (1.7 g, 11.72 mmol) in water (4 ml) was slowly added
dropwise thereto. After 30 minutes, a solution of sodium
fluoroborate (3.2 g, 28.79 mmol) in water (20 ml) was slowly added
dropwise to the reaction solution at -10.degree. C., followed by
stirring at the same temperature for 1 hour. Next, the reaction
solution was heated to room temperature and stirred for 1 hour. The
produced solid was filtered under reduced pressure, washed with
cold ice water and methanol, and then dried under reduced pressure,
after which toluene (20 ml) was added thereto, followed by heating
at 120.degree. C. for 2 hours. The reaction solution was cooled to
room temperature, and cold ice water was added thereto to terminate
the reaction. Next, the reaction solution was extracted with ethyl
acetate and washed with an aqueous solution of sodium chloride. The
separated organic layer was dried with anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexane:ethyl acetate=15:1) to afford the
title compound (1.8 g; yield: 81%) as colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 6.99 (dd, J=8.2 Hz, 5.4
Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 3.92 (s, 3H), 2.26 (s, 3H), 2.20
(d, J=2.0 Hz, 3H).
Step 2: Synthesis of
2-(chloromethyl)-4-fluoro-1,3-dimethylbenzene
The compound (1.8 g, 10.15 mmol) was reacted in the same manner as
described in steps 5 and 6 of Reference Example 3, thereby
obtaining the title compound (1.3 g; yield: 77%) as colorless
oil.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 6.99 (dd, J=8.2 Hz, 5.8
Hz, 1H), 6.90 (t, J=9.0 Hz, 1H), 4.62 (s, 2H), 2.38 (s, 3H), 2.32
(d, J=2.0 Hz, 3H).
Example 1:
{8-[(2,6-Dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]-
pyridin-6-yl}(3-hydroxyazetidin-1-yl)methanone
Step 1: Synthesis of isopropyl
8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-.alpha.]pyridine-6-ca-
rboxylate
To isopropyl
8-amino-2,3-dimethylimidazo[1,2-.alpha.]pyridine-6-carboxylate (59
g, 18.0 mmol), anhydrous 2-propanol (590 ml) was added, and
potassium carbonate (59 g, 44.9 mmol) and sodium iodide (15 g, 10.0
mmol) were sequentially added thereto. The mixture was heated to
70.degree. C. At the same temperature, a solution of
2,6-dimethylbenzyl chloride (31 g, 20.0 mmol) in anhydrous
2-propanol (60 ml) was slowly added dropwise top the reaction
mixture, followed by stirring for 4 hours. Thereafter, a solution
of 2,6-dimethylbenzyl chloride (17 g, 10.8 mmol) in potassium
chloride (54.7 g, 39.5 mmol) and anhydrous 2-propanol (20 ml) was
added to the reaction solution, followed by stirring for 6 hours.
At room temperature, the reaction was terminated by addition of
water, and the reaction solution was stirred for 30 minutes. The
produced solid was filtered, washed sequentially with water and
cold 2-propanol, and then dried, thereby obtaining the title
compound (55 g; yield: 88%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 8.25 (s, 1H), 7.30 (s,
1H), 7.15-7.09 (m, 1H), 7.06-7.04 (m, 2H), 6.73 (s, 1H), 5.31-5.26
(m, 1H), 4.84 (br, 1H), 4.41 (d, J=4.4 Hz, 2H), 2.39 (s, 12H), 1.40
(d, J=6.4 Hz, 6H).
Step 2: Synthesis of
8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo[1,2-.alpha.]pyridine-6-ca-
rboxylic acid
The compound (92.5 g, 25.3 mmol) prepared in step 1 was dissolved
in ethanol (920 ml), and a 2N aqueous solution of sodium hydroxide
(500 ml) was added to the solution at room temperature, followed by
stirring at 80.degree. C. for 2 hours. The reaction solution was
cooled to room temperature and concentrated under reduced pressure
the solvent, after which water was added to the residue and a 2N
aqueous solution of hydrochloric acid (500 ml) was slowly added
dropwise to the aqueous solution at 0.degree. C. to adjust the pH
to about 5. Next, the solution was stirred for 8 hours, filtered,
washed with water, and then dried, thereby obtaining the title
compound (69 g; yield 85%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3+CD.sub.3OD); .delta. 8.36 (s, 1H),
7.32 (s, 1H), 7.16-7.14 (m, 1H), 7.11-7.10 (m, 2H), 4.50 (s, 2H),
2.52 (s, 3H), 2.42 (s, 9H).
Step 3: Synthesis of
{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-.alpha.]pyridin-6--
yl}(3-hydroxyazetidin-1-yl)methanone
The compound (30 mg, 0.06 mmol) prepared in step 2 was dissolved in
anhydrous dichloromethane (5 ml). Then,
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide chloride (EDCI, 18
mg, 0.09 mmol), 1-hydroxy-benzotriazole hydrate (HOBt, 13 mg, 0.09
mmol), 3-hydroxyazetidine (8.1 mg, 0.07 mmol) and triethylamine (34
.mu.l, 0.25 mmol) were sequentially added to the solution at
0.degree. C., followed by stirring at room temperature for 22
hours. Next, an aqueous solution of sodium bicarbonate was slowly
added to the reaction solution at 0.degree. C. to terminate the
reaction, and the reaction solution was extracted with
dichloromethane. The separated organic layer was washed with a
saturated aqueous solution of sodium chloride, dried with anhydrous
sodium sulfate, and then concentrated under reduced pressure. The
residue was purified by column chromatography (hexane:ethyl
acetate=3:1) to afford the title compound (35 mg; yield: 95%) as a
white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.62 (s, 1H), 7.14-7.10
(m, 1H), 7.05-7.03 (m, 2H), 6.39 (s, 1H), 4.92 (br, 1H), 4.77-4.71
(m, 1H), 4.53-4.49 (m, 2H), 4.14 (d, J=6.8, 2H), 4.15-4.13 (m, 2H),
2.38-2.34 (m, 12H).
Based on the reaction procedure described in Example 1, compounds
of Examples 2 to 48, which have different substituents as shown in
Table 1 below, were synthesized.
TABLE-US-00001 Example Chemical structure Yield NMR spectrum data 2
##STR00004## 79% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(S, 1H), 7.15-7.11 (m, 1H), 7.06-7.04 (m, 2H), 6.37 (s, 1H),
5.30-5.27 (m, 1H), 4.80- 4.95 (m, 1H), 4.70-4.50 (m, 2H), 4.37 (d,
J = 4.0 Hz, 2H), 4.30-4.20 (m, 2H), 2.38- 2.34 (m, 12H), 2.13 (s,
3H) 3 ##STR00005## 26% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta.
7.63 (s, 1H), 7.14-7.10 (m, 1H), 7.05-7.03 (m, 2H), 6.39 (s, 1H),
4.91 (m, 1H), 4.45 (br, 2H), 4.37 (d, J = 4.0 Hz, 2H), 4.30-4.27
(m, 1H), 4.17 (br, 2H), 3.34 (s, 3H), 2.37-2.34 (m, 12H) 4
##STR00006## 26% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.63
(s, 1H), 7.14-7.09 (m, 1H), 7.05-7.01 (m, 2H), 6.39 (s, 1H), 4.86
(br, 1H), 4.56 (br, 2H), 4.37 (d, J = 5.6 Hz, 2H), 4.15-4.12 (m,
2H), 3.50-3.48 (qt, 2H), 2.37-2.29 (m, 12H), 1.26 (t, J = 7.0 Hz,
3H) 5 ##STR00007## 35% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta.
7.62 (s, 1H), 7.14-7.11 (m, 1H), 7.08-7.03 (m, 2H), 6.39 (s, 1H),
4.86 (m, 1H), 4.45-4.36 (m, 7H), 3.60-3.57 (m, 4H), 3.40 (s, 3H),
2.37-2.34 (m, 12H) 6 ##STR00008## 85% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.63 (d, J = 1.2 Hz, 1H) 7.13 (dd, J = 8.4,
6.8 Hz, 1H) 7.06-7.04 (m, 2H) 6.42 (d, J = 1.2 Hz, 1H), 4.86-4.84
(m, 1H), 4.41-4.28 (m, 4H), 4.37 (d, J = 4.4 Hz, 2H), 3.75-3.69 (m,
1H), 2.43-2.34 (m, 13H) 7 ##STR00009## 59% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.63 (s, 1H), 7.14-7.10 (m, 1H), 7.05-7.03 (m,
2H), 6.36 (s, 1H), 5.48-5.45 (m, 0.5H), 5.33- 5.29 (m, 0.5H), 4.90
(br, 1H), 4.58- 4.36 (m, 6H), 2.37-2.34 (m, 12H) 8 ##STR00010## 84%
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.63 (d, J = 1.2 Hz,
1H), 7.13 (dd, J = 8.4, 6.8 Hz, 1H), 7.06-7.04 (m, 2H), 6.42 (d, J
= 1.6 Hz, 1H), 4.90-4.88 (m, 1H), 4.51 (br, 2H, 4.38 (d, J = 4.0
Hz, 2H 3.95-3.82 (m, 1H), 2.87-2.79 (m, 1H), 2.38-2.34 (m, 12H),
1.32 (d, J = 6.8 Hz, 1H) 9 ##STR00011## 72% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.60 (s, 1H), 7.14-7.10 (m, 1H), 7.05-7.03 (m,
1H), 6.41 (m, 1H), 5.08 (br, 1H), 4.35 (d, J = 4.0 Hz, 2H)
4.15-4.12 (m, 4H), 2.38- 2.33 (m, 12H), 2.05 (s, 3H) 10
##STR00012## 85% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(d, J = 1.6 Hz, 1H) 7.13-7.11 (m, 1H), 7.06- 7.04 (m, 2H), 6.38 (S,
1H), 4.83-4.86 (m, 1H), 4.62-4.40 (m, 4H), 4.37 (d, J = 4.4 Hz,
2H), 3.80 (s, 3H), 3.60-3.50 (m, 1H), 2.38-2.34 (m, 12H) 11
##STR00013## 79% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(d, J = 1.6, 1H), 7.64 (dd, J = 8.8, 6.8 Hz, 1H), 7.06-7.04 (H,
2H), 6.43 (S, 1H), 4.92 (br, 1H), 4.44-4.01 (m, 4H), 4.37 (d, J =
4.4 Hz, 2H), 3.84 (d, J = 5.6 Hz, 2H), 2.87-2.82 (m, 1H), 2.38-2.36
(m, 12H) 12 ##STR00014## 99% .sup.1H NMR (400 MHz, CDCl.sub.3);
.delta. 7.65 (d, J = 1.6 Hz), 7.15-7.11 (m, 1H), 7.06- 7.04 (m,
1H), 6.42 (s, 1H), 4.85 (br, 1H), 4.47-3.99 (m, 1H), 4.37 (d, J =
4.4 Hz, 2H), 3.59 (d, J = 6.4, 2H), 3.0-2.92 (m, 1H), 2.38-2.34 (m,
12H), 2.18 (s, 3H) 13 ##STR00015## 53% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.65 (s, 1H), 7.14-7.11 (m, 1H), 7.05-7.04 (m,
2H), 6.37 (s, 1H), 4.91 (br, 1H), 4.41-4.37 (m, 6H), 3.93 (d, J =
20.8, 2H), 2.38-2.34 (m, 12H) 14 ##STR00016## 57% .sup.1H NMR (400
MHz, CDCl.sub.3); .delta. 7.64 (s, 1H), 7.11 (dd, J = 8.0, 6.4 Hz,
1H), 7.03 (m, 2H), 6.43 (s, 1H), 4.93-4.91 (m, 1H), 4.36 (d, J =
4.4 Hz, 2H), 4.29-3.85 (m, 4H), 3.47 (d, J = 0.8 Hz, 2H), 2.37 (s,
6H), 2.34 (d, J = 7.6 Hz, 6H), 1.32 (S, 3H) 15 ##STR00017## 76%
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64 (d, J = 1.2 Hz,
1H), 7.13 (dd, J = 8.8, 6.8 Hz, 1H), 7.05-7.04 (S, 1H), 6.42 (s,
1H), 4.87-4.86 (m, 1H), 4.67 (d, J = 4.4 Hz, 2H), 4.36-4.01 (m,
4H), 2.68 (m, 1H), 2.38- 2.34 (m, 12H), 1.21 (d, J = 6.4 Hz, 3H) 16
##STR00018## 34% .sup.1NMR (400 MHz, CDCl.sub.3); .delta. 7.63 (d,
J = 1.2 Hz, 1H), 7.11 (dd, J = 6.8, 6.4 Hz, 1H), 7.04-7.03 (m, 2H),
6.42 (s, 1H), 4.90 (br, 1H), 4.37 (d, J = 1.1 Hz, 2H), 4.31-4.11
(m, 4H), 2.701 (m, 1H), 2.37- 2.33 (m, 12H), 1.21 (s, 6H) 17
##STR00019## 48% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.65
(s, 1H), 7.13 (dd, J = 8.4, 6.8 Hz, 1H), 7.06- 7.04 (m, 2H), 6.41
(S, 1H), 4.93-4.83 (m, 3H), 4.38-4.30 (m, 4H), 3.97-3.92 (m, 1H),
3.83-3.81 (m, 1H), 2.44-2.35 (m, 13H), 2.14-2.06 (m, 1H) 18
##STR00020## 68% .sup.1H NMR (400 MHz, CDCl.sub.3); 7.64 (d, J =
1.2 Hz, 1H), 7.15-7.11 (m, 1H), 7.06- 7.04 (m, 2H), 6.39 (m, 2H),
4.92-4.89 (m, 1H), 4.60 (br, 1H), 4.46-4.37 (m, 4H), 4.28 (br, 1H),
3.67-3.58 (m, 1H), 2.38- 2.34 (m, 12H), 2.25 (S, 3H) 19
##STR00021## 74% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(s, 1H), 7.15-7.11 (m, 1H), 7.06-7.04 (m, 2H), 6.33 (sm 1H), 4.93
(br, 1H), 4.62-4.54 (m, 4H), 4.37 (d, J = Hz, 2H), 4.12-4.05 (m,
1H), 2.95 (s, 3H), 2.38-2.34 (m, 12H) 20 ##STR00022## 40% .sup.1H
NMR (400 MHz, CDCl.sub.3); .delta. 7.63 (d, J = 0.8 Hz, 1H), 7.12
(dd, J = 8.4, 6.8 Hz, 1H), 7.05-7.03 (m, 2H), 6.42 (s, 1H),
4.91-4.90 (m, 1H), 4.49-4.31 (m, 4H), 4.15-4.09 (m, 2H), 4.04-3.91
(m, 2H), 3.67 (t, J = 5.8 Hz, 3H), 2.89-2.82 (m, 1H), 2.38-2.34 (m,
12H) 21 ##STR00023## 67% .sup.1H NMR (400 MHz, CD3OD); .delta. 8.56
(s, 1H), 7.20-7.09 (m, 4H), 4.57-.316 (m, 12H), 2.64-2.42 (m, 12H)
22 ##STR00024## 98% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.62
(s, 1H), 7.15-7.11 (m, 1H), 7.06-7.04 (m, 2H), 6.36 (s, 1H), 4.93
(m, 1H), 4.85 (br, 4H), 4.46 (br, 4H), 4.37 (d, J = 4.4, 2H), 2.38-
2.35 (m, 12H) 23 ##STR00025## 82% .sup.1H NMR (400 MHz, CDCl3);
.delta. 7.66 (s, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 4.0
Hz, 2H), 7.16-7.14 (m, 1H), 6.14 (s, 1H), 5.46 (br, 1H), 4.69-4.63
(m, 1H), 4.44- 4.22 (m, 4H), 3.99-3.98 (m, 2H), 2.38- 2.37 (m, 9H)
24 ##STR00026## 38% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.67
(d, J = 1.6 Hz, 1H), 7.15 (br, 1H), 7.09- 7.08 (m, 1H), 7.02-7.00
(m, 1H), 6.15 (S, 1H), 5.35 (m, 1H), 4.72-4.62 (m, 1H), 4.40-4.38
(m, 4H), 4.02-4.00 (m, 2H), 2.39-2.26 (m, 9H) 25 ##STR00027## 81%
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.61 (d, J = 1.6 Hz,
1H), 7.19 (t, J = 8.0, 7.6 Hz, 1H), 6.82, (d, J = 7.6 Hz, 1H), 6.79
(d, J = 8 Hz, 2H), 6.46 (d, J = 1.2, 1H), 4.69- 4.63 (m, 1H),
4.52-4.60 (m, 4H), 4.25 (br, 1H), 4.02 (br, 1H), 3.84 (S, 3H),
3.38- 3.36 (m, 1H), 2.41 (S, 3H), 2.37 (S, 3H), 2.33 (S, 3H) 26
##STR00028## 43% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.62
(d, J = 1.2 Hz, 1H), 7.17 (t, J = 8.4, 7.6 Hz, 1H), 6.80 (d, J =
8.0 Hz, 2H), 6.75 (d, J = Hz, 2H), 6.44 (S, 1H), 5.08-5.07 (m, 1H),
4.43-4.42 (m, 3H), 4.26-4.09 (m, 2H), 3.97 (br, 1H), 3.81 (S, 2H),
3.80 (S, 3H), 2.38-2.34 (m, 9H) 27 ##STR00029## 72% .sup.1H NMR
(400 MHz, CD.sub.3OD); .delta. 7.78 (s, 1H), 7.33 (dd, J = 8.0 Hz,
6.0 Hz, 1H), 6.98-6.96 (m, 1H), 6.89-6.85 (M, 1H), 6.28 (s, 1H),
4.62 (s, 2H), 4.32-4.28 (m, 1H), 4.20-4.16 (m, 1H), 4.00 (m, 1H),
3.92 (m, 1H), 2.81 (m, 1H), 2.41 (s, 6H), 2.35 (s, 3H) 28
##STR00030## 77% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.67
(d, J = 1.6, 1H), 7.29-7.28 (m, 1H), 6.93- 6.90 (m, 1H), 6.85-6.80
(m, 1H), 6.19 (s, 1H), .delta. 4.40 (d, J = 5.6 Hz, 2H), 4.19 (br,
4H), 2.40-2.28 (m, 14H) 29 ##STR00031## 85% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.67 (S, 1H), 7.30-7.27 (m, 1H), 6.94-6.91 (m,
1H), 6.86-6.82 (m, 1H), 6.12 (S, 1H), 5.41- 5.38 (m, 1H), 5.27-5.24
(m, 1H), 4.400- 4.22 (m, 6H), 2.39-2.38 (m, 9H) 30 ##STR00032## 71%
.sup.1H NMR (MHz, CDCl.sub.3); .delta. 7.67 (d, J = 2.4 Hz, 1H),
7.30-7.27 (m, 1H), 6.93- 6.90 (m, 1H), 6.85-6.81 (m, 1H), 6.16 (d,
J = 1.2 Hz, 1H), 5.33-5.31 (m, 1H), 4.39 (d, J = 5.2, 1H), 4.27
(br, 2H), 3.86-3.68 (m, 2H), 2.76-7.71 (m, 1H), 2.38 (S, 9H), 1.26
(d, J = 6.8 Hz, 3H) 31 ##STR00033## 68% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.66 (S, 1H), 7.30-7.26 (m, 1H), 6.93-6.90 (m,
1H), 6.86-6.81 (m, 1H), 6.14 (S, 1H), 5.38- 5.36 (m, 1H), 4.38 (d,
J = 4.8 Hz, 2H), 4.10-3.90 (m, 4H), 2.38 (S, 9H), 1.53 (S, 3H) 32
##STR00034## 81% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(S, 1H), 7.12 (dd, J = 8.4, 7.2 Hz, 1H), 7.05- 7.03 (m, 2H), 6.40
(S, 1H), 4.87 (br, 1H), 4.38-4.37 (m, 2H), 4.30-4.06 (m, 4H), 3.29
(s, 3H), 2.38-2.34 (m, 12H), 1.54 (S, 3H) 33 ##STR00035## 80%
.sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.67 (d, J = 1.6 Hz,
1H), 7.30-7.27 (m, 1H), 6.93- 6.90 (m, 1H), 6.86-6.81 (m, 1H), 6.17
(d, J = 1.2, 1H), 5.35-5.31 (m, 1H), 4.39 (d, J = 5.2, 2H), 4.22
(br, 2H), 3.96-3.92 (m, 2H), 3.81-3.80 (m, 2H), 2.85-2.82 (m, 1H),
2.38 (S, 9H) 34 ##STR00036## 43% .sup.1H NMR (400 MHz, CDCl.sub.3);
.delta. 7.62 (d, J = 1.2 Hz, 1H), 6.76 (d, J = 9.6, 2H), 6.40 (d, J
= 1.2 Hz, 1H), 4.86 (br, 1H), 4.78-4.73 (m, 1H), 4.54-4.53 (m, 2H),
4.31 (d, J = 4.4 Hz, 2H), 4.16 (br, 2H), 2.37-2.35 (m, 12H) 35
##STR00037## 95% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.63
(s, 1H), 6.76 (d, J = 9.6 Hz, 2H), 6.42 (s, 1H), 4.79 (br, 1H),
4.41-4.27 (m, 4H), 4.32 (d, J = 4.4 Hz), 2.43-2.35 (m, 14H) 36
##STR00038## 83% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(s, 1H), 6.77 (d, J = 9.6, 2H), 6.37 (sm 1H), 5.50- 5.45 (m, 0.5H),
5.36-5.30 (m, 0.5H), 4.85 (br, 1H), 4.63-4.41 (m, 4H), 4.32 (d, J =
4.0 Hz, 2H), 2.38-2.35 (m, 12H) 37 ##STR00039## 76% .sup.1H NMR
(400 MHz, CDCl.sub.3); .delta. 7.64 (d, J = 1.6 Hz, 1H), 6.76 (d, J
= 9.6 Hz, 2H), 6.42 (d, J = 1.2 Hz, 1H), 4.80 (br, 1H), 4.51-4.32
(m, 4H), 3.97-3.83 (m, 2H), 2.87-2.80 (m, 1H), 2.38-2.35 (m, 12H),
1.32 (d, J = 7.2 Hz, 3H) 38 ##STR00040## 84% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.61 (s, 1H), 6.75 (d, J = 9.6, 2H), 6.40 (s,
1H), 4.94 (br, 1H), 4.30 (d, J = 4.0 Hz, 2H), 4.19-4.09 (m, 4H),
2.36-2.34 (m, 12H), 1.55 (s, 3H) 39 ##STR00041## 80% .sup.1H NMR
(400 MHz, CDCl.sub.3); .delta. 7.64 (d, J = 1.2 Hz, 1H), 6.76 (d, J
= 10 Hz, 2H), 6.42 (d, J = 1.2 Hz, 1H), 4.83 (br, 1H), 4.53-4.01
(m, 4H), 4.32 (d, J = 4.4 Hz, 2H), 3.86 (d, J = 6.4 Hz, 2H),
2.92-2.88 (m, 1H), 2.37-2.35 (m, 12H) 40 ##STR00042## 61% .sup.1H
NMR (400 MHz, CDCl.sub.3); .delta. 7.65 (S, 1H), 6.76 (d, J = 9.6,
2H), 6.42 (S, 1H), 4.80 (m, 1H), 4.45-3.99 (m, 6H), 3.58 (d, J =
6.4, 2H), 3.40 (S, 3H), 2.97-2.94 (m, 1H), 2.37-2.34 (m, 12H) 41
##STR00043## 50% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(S, 1H), 7.05-7.02 (m, 1H), 6.95-6.90 (m, 1H), 6.42 (S, 1H),
4.68-4.66 (m, 1H), 4.53- 4.06 (m, 7H), 2.41-2.29 (m, 14H) 42
##STR00044## 99% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64
(d, J = 1.6 Hz, 1H), 7.02-6.98 (m, 1H), 6.94- 6.89 (m, 1H), 6.44
(s, 1H), 4.89 (br, 1H), 4.37-4.29 (m, 6H), 2.42-2.27 (m, 14H) 43
##STR00045## 73% .sup.1H NMR (400 MHz, CDCl3); .delta. 7.64 (d, J =
1.2 Hz, 1H), 7.02-6.99 (m, 1H), 6.94- 6.90 (m, 1H), 6.38 (d, J =
1.2 Hz, 1H), 5.50-5.45 (m, 0.5H), 5.36-5.31 (m, 0.5H), 4.82-4.87
(m, 1H), 4.60-4.53 (m, 2H), 4.53-4.35(m, 5H), 2.38-2.27 (m, 12H) 44
##STR00046## 73% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.65
(d, J = 1.6 Hz, 1H), 7.02-6.98 (m, 1H), 6.93- 6.89 (m, 1H), 6.43
(d, J = 0.8 Hz, 1H), 4.87 (br, 1H), 4.44-4.00 (m, 4H), 4.35 (d, J =
4.4, 2H), 3.86-3.85 (d, J = 5.6, 2H), 2.95-2.85 (m, 1H), 2.37-2.33
(m, 9H), 2.27 (d, J = 2.0 Hz, 3H) 45 ##STR00047## 73% .sup.1H NMR
(400 MHz, CDCl.sub.3); .delta. 7.64 (d, J = 1.2 Hz, 1H), 7.25 (d, J
= 8.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 1.2 Hz, 1H),
4.83-4.81 (m, 1H), 4.39-4.28 (m, 4H), 4.38 (d, J = 4.4 Hz, 2H),
2.44- 2.35 (m, 14H) 46 ##STR00048## 84% .sup.1H NMR (400 MHz,
CDCl.sub.3); .delta. 7.64 (S, 1H), 7.27-7.23 (m, 1H), 7.00-6.98 (m,
1H), 6.40 (S, 1H), 4.92-4.86 (m, 1H), 4.60- 4.50 (m, 1H), 4.38 (d,
J = 4.0 Hz, 2H), 4.15 (br, 2H, 2.42-2.35 (m, 12H) 47 ##STR00049##
90% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.64 (d, J = 1.2 Hz,
1H), 7.27-7.24 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H),
5.50-5.45 (m, 0.5H), 5.36-5.31 (m, 0.5H), 4.87-4.85 (m, 1H),
4.63-4.54 (m, 2H), 4.53-4.38 (m, 5H), 2.42-2.35 (m, 12H) 48
##STR00050## 75% .sup.1H NMR (400 MHz, CDCl.sub.3); .delta. 7.65
(s, 1H), 7.26-7.23 (m, 1H), 7.00-6.98 (m, 1H), 6.43 (s, 1H),
4.89-4.87 (m, 1H), 4.44- 3.99 (m, 4H), 4.37 (d, J = 4.0 Hz, 2H),
3.84 (d, J = 5.6, 2H), 2.92-2.85 (m, 1H), 2.41-2.35 (m, 12H)
Test Example 1: Preparation of Gastric Vesicles
Gastric vesicles used in the experiment were prepared by separation
from porcine gastric mucosa according to a centrifugation method
[Saccomani G, et al., A Nonelectrogenic H.sup.+ Pump in Plasma
Membranes of Hog Stomach, J Biol Chem., 1976, 251 (23), 7690-8].
Next, the protein content of the gastric vesicles was quantified
using a bicinchoninic acid kit [Smith P K, et al., Measurement of
protein using bicinchoninic acid, Anal Biochem., 1985, 150 (1),
76-85)].
Test Example 2: Measurement of Inhibitory Effects Against Proton
Pump (H.sup.+/K.sup.+-ATPase) Activity
The inhibitory effects of the compounds against proton pump
activity were calculated based on the pump activity determined in
the presence of K.sup.+ ions excluding the pump activity determined
in the absence of K.sup.+ ions. The inhibitory effects against
proton pump activity were measured in 96-well plates, and all
reactions were performed with a reaction volume of 100 .mu.m at
37.degree. C. Specifically, 10 .mu.m of valinomycin and each
concentration of each compound were pre-incubated in a reaction
buffer (50 mmol/L Tris-Hepes buffer, pH 6.4) containing porcine
gastric vesicles for 15 minutes. For negative and positive control
groups, 1% DMSO was added to buffer, and for test groups, 1% DMSO
and a dilution of each concentration of each compound were added.
Next, 0.2 mmol/L of adenosine triphosphate (ATP) was added to the
reaction buffer and incubated at 37.degree. C. for 40 minutes.
After completion of the incubation, a malachite green solution was
added to the reaction buffer and incubated for 30 minutes, and the
amount of inorganic phosphate in the reaction buffer was measured
by colorimetry using a malachite green phosphate assay Kit
(Bioassay Systems). For colorimetry, the OD (optical density) at
620 nm was measured using a microplate reader [Synergy H4, hybrid
multimode microplate reader, BioTek]. The percent inhibition of
proton pump (H.sup.+/K.sup.+-ATPase) was determined based on the OD
value of the control group and the OD values of various
concentrations of the test compounds, and the IC.sub.50 of each
test compound was calculated using the Logistic 4-parameter
function of Sigmaplot 8.0 program. The results are shown in Table 2
below.
TABLE-US-00002 TABLE 2 Example IC.sub.50 (.mu.M) 1 0.020 2 0.128 3
0.090 4 0.093 5 0.117 6 0.017 7 0.055 8 0.096 9 0.069 10 0.048 11
0.039 12 0.065 13 0.119 14 0.104 15 0.072 16 0.122 17 0.180 18
0.140 19 0.117 20 0.046 21 0.600 22 0.079 23 0.374 27 0.135 28
0.103 29 0.645 30 0.271 31 0.662 32 0.187 33 0.143 34 0.028 35
0.016 36 0.029 37 0.021 38 0.041 39 0.024 40 0.134 41 0.149 42
0.085 43 0.174 44 0.061 45 0.081 46 0.163 47 0.624 48 0.102
As can be seen in Table 2 above, the compounds of the present
disclosure have excellent inhibitory effects against gastric
H.sup.+/K.sup.+-ATPase.
Test Example 3: Inhibitory Effects against Esophageal Injury in
Reflux Esophagitis Models
The inhibitory effects of the compounds of the present disclosure
against esophageal injury in reflux esophagitis models were
evaluated according to the method of Nakamura [Nakamura K, et al.,
Effects of sodium polyacrylate (PANa) on acute esophagitis by
gastric juice in rats, Jpn J Pharmacology, 1982, 32, 445-56].
Male Sprague Dawley (SD) rats (weighing 180-210 g) were divided
into X groups (n=6) and fasted without water for 24 hours. Then,
the control group was administered orally with only 10% DMSO, 10%
Cremophor EL and 80% water, and the other groups were administered
orally with 2 mg/kg/2 ml of each test compound together with 10%
DMSO, 10% Cremophor EL and 80% water. At 1 hour after
administration of the excipients and each compound, the abdominal
cavity of each rate was incised under isoflurane anesthesia, and
the pylorus was ligated, and the boundary between the anterior
portion and the body was also ligated. At 6 hours after ligation,
the test animals were euthanized, and the esophagus ranging from
the thyroid to the cardiac portion was carefully extracted. The
extracted esophagus was incised in a longitudinal direction and
spread so as to expose the mucosa and was then fixed, after which
the area of esophageal injury was measured. The results are shown
in Table 3 below.
Percent (%) inhibitory activity of test compounds={(total
esophageal injury area of control group-esophageal injury area of
group treated with test compound)/total esophageal injury area of
control group}.times.100.
TABLE-US-00003 TABLE 3 Example GERD (rat/mpk) 1 84.0% 6 100.0% 7
100.0% 8 95.4% 9 77.2% 11 97.6% 33 92.7% 34 91.4% 36 98.2% 39
98.4%
As can be seen in Table 3 above, the compounds of the present
disclosure have strong inhibitory effects against esophageal injury
in reflux esophagitis models.
Test Example 4: Inhibitory Effects against Histamine-Stimulated
Gastric Acid Secretion in Pylorus-Ligated Rats
The inhibitory effects of the compounds of the present disclosure
against histamine-stimulated gastric acid secretion were evaluated
using Shay's rat models [Shay H, et al. A simple method for the
uniform production of gastric ulceration in the rat,
Gastroenterology, 1945, 5, 43-61].
Male Sprague-Dawley (SD) rats (weighing 180-210 g) were divided
into X groups (n=7) and fasted with only water access for 24 hours.
At 1 hour before pylorus ligation, the control group was
administered orally with only 10% DMSO, 10% Cremophor EL and 80%
water, and the other groups were administered orally with 2 mg/kg/2
ml of each compound together with 10% DMSO, 10% Cremophor EL and
80% water. The abdominal cavity of each rate was incised under
isoflurane anesthesia, and the pylorus was ligated. Immediately
after ligation, histamine 2HCl was administered subcutaneously to
each rat at a dose of 30 mg/kg/10 ml. At 3 hours after ligation,
the test animals were euthanized, and the gastric content was
extracted. The extracted gastric content was centrifuged at
3,000.times.g for 10 minutes, and the supernatant was collected to
obtain gastric juice. Next, the acidity of the gastric juice was
determined based on the volume of (ueq/ml) of 0.1 N--NaOH required
for automatic titration of the gastric juice to pH 7.0, and the
acidity of the gastric juice was multiplied by the amount of the
gastric juice to determine total acid output. The results are shown
in Table 4 below.
Percent (%) inhibitory activity of test compounds={(total acid
output in control group-total acid output in group treated with
test compound)/total acid output in control group}.times.100.
TABLE-US-00004 TABLE 4 Example acid output (rat/2 mpk) 1 71% 6 94%
7 91% 11 78%
As can be seen in Table 4 above, the compounds of the present
disclosure have string inhibitory activities against
histamine-stimulated gastric acid secretion in pylorus-ligated
rats.
Test Example 5: Inhibition of Acid Secretion in Lumen-Perfused
Rats
The inhibitory effects of the compounds of the present disclosure
against histamine-stimulated gastric acid secretion in
lumen-perfused rat models were evaluated using the method of Ghosh
& Schild [Ghosh M N, et al. Continuous recording of acid
gastric secretion in the rat, Br J Pharmacol Chemother., 1958, 13
(1), 54-61].
Male Sprague-Dawley (SD) rats (weighing 250-300 g) were divided
into X groups (n=4) and fasted with only water access for 24 hours.
Each of the rats was anesthetized by intra-abdominal administration
of urethane (1.2 g/kg), and then the abdominal cavity was incised,
and the boundary between the boundary between the anterior portion
and the body was ligated. A silicone tube was inserted between the
stomach and the esophagus so that saline (pH 5.0) would be
perfused. Furthermore, a silicone tube was inserted between the
pylorus and the duodenum so that the perfusate that passed through
the stomach flowed out. Then, histamine 2HCl (8 mg/kg) was infused
through the jugular vein to stabilize the gastric pH. After pH
stabilization, the control group was administered intravenously
with only 10% DMSO, 10% Cremophor EL and 80% water, and the other
groups were administered intravenously with 2 mg/kg/2 ml of each
compound together with 10% DMSO, 10% Cremophor EL and 80% water.
After drug administration, the perfusate was collected at 10-minute
intervals for 5 hours, and the pH thereof was measured. The results
are shown in FIG. 1.
As can be seen in FIG. 1, the compounds of the present disclosure
have strong and long-lasting inhibitory activities against
histamine-stimulated gastric acid secretion in lumen-perfused
rats.
* * * * *